EP2398808A1 - Process for the reductive alkylation of normorphinans - Google Patents

Process for the reductive alkylation of normorphinans

Info

Publication number
EP2398808A1
EP2398808A1 EP10704301A EP10704301A EP2398808A1 EP 2398808 A1 EP2398808 A1 EP 2398808A1 EP 10704301 A EP10704301 A EP 10704301A EP 10704301 A EP10704301 A EP 10704301A EP 2398808 A1 EP2398808 A1 EP 2398808A1
Authority
EP
European Patent Office
Prior art keywords
chosen
hydrogen
formula
group
formic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP10704301A
Other languages
German (de)
French (fr)
Other versions
EP2398808B1 (en
Inventor
Edmund C. Hudson
Sharon Woods
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mallinckrodt LLC
Original Assignee
Mallinckrodt LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mallinckrodt LLC filed Critical Mallinckrodt LLC
Priority to PL10704301T priority Critical patent/PL2398808T3/en
Publication of EP2398808A1 publication Critical patent/EP2398808A1/en
Application granted granted Critical
Publication of EP2398808B1 publication Critical patent/EP2398808B1/en
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • the present invention generally relates to a method for the synthesis of N-alkylated morphinans.
  • the process provides a method for reducing an iminium salt formed from the reaction of a normorphinan and a carboxaldehyde,
  • N-aikylated morphinans are important pharmaceuticals, typically used as analgesics, opiate agonists, and opiate antagonists. With the increasing use of these agents, a practical and effective method of preparation of these compounds is vital to synthesizing diverse N-alkyl substituted morphinans.
  • N-alkylated morphinans have at least one of two primary limitations: (a) their dependence on a transition metal catalyst, and (b) the use of hydrogen gas as a source of hydrogen for the alkylation.
  • Transition metal catalysts are expensive and toxic, which requires testing of the finished product to ensure that the final product does not contain more than a specified parts per million of the transition metal, Additionally, hydrogen gas is hazardous, and methods of synthesis typically employ high pressures.
  • Some prior art methods have incorporated a borohydride to catalyze the reaction. It was desired to avoid this method because the side products are difficult to separate from the desired product, and the reactions may require lower temperatures, -20° to - 30° C, when a keto group is present.
  • the present invention provides processes for the synthesis of N-alkylated morphinans from the corresponding normorphinan compounds.
  • One aspect of the present invention encompasses a process for the preparation of an N- aikylated morphinan.
  • the method comprises contacting a normorphinan comprising a secondary amine at position 17 with an alkylating agent comprising R 10 , wherein R 10 is selected from the group consisting of hydrocarbyi and substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form the N-alkylated morphinan comprising NR 10 at position 17.
  • R 10 is selected from the group consisting of hydrocarbyi and substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form the N-alkylated morphinan comprising NR 10 at position 17.
  • the current invention encompasses a process for the preparation of a compound comprising Formula (IiIa).
  • the process comprises: (a) contacting a compound comprising Formuia (Ia) with an alkylating agent comprising R 10 in the presence of a proton acceptor to form a compound comprising Formula (Ha); and (b) contacting the compound comprising Formula (Ha) with a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form a compound comprising Formuia (Ilia) according to the following reaction scheme:
  • R 2 , R 6 , and R 7 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and ⁇ - ⁇ 0R 11 ;
  • R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ 0R 11 ;
  • R 5 is selected from the group consisting of hydrogen, and hydroxyl
  • Rio is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl
  • R 11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group
  • X is selected from the group consisting of oxygen and sulfur.
  • the current invention encompasses a process for the preparation of a compound comprising Formula (lllb).
  • the process comprises: (a) contacting a compound comprising Formula (Ib) with an alkylating agent comprising R 10 in the presence of a proton acceptor to form a compound comprising Formula (lib); and (b) contacting the compound comprising Formula (lib) with a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form a compound comprising Formula (IHb) according to the following reaction scheme:
  • R 1 , R 2 , R 6 , R 7 , and R 9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and ⁇ - ⁇ 0R 11 ;
  • R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and HOR 11 ;
  • R 5 is selected from the group consisting of hydrogen, and hydroxyl
  • R 10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl
  • R 11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy! protecting group.
  • the present invention provides an efficient process for the production of N-alkylated morphinans in high yield,
  • the process of the present invention avoids the use of toxic metal catalysts and dangerous hydrogen gas.
  • the process of the invention may be conducted in a one-pot process, without isolation or purification of the intermediate products.
  • One aspect of the present invention provides an efficient process for the production of N- alkylated morphinan compounds.
  • the process comprises contacting a normorphinan comprising a secondary amine at position 17 with an alkylating agent comprising R 10 , wherein R 10 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof to form the N-alkylated morphinan comprising NR 10 at position 17.
  • the normorphinan comprises any compound having a morphinan structure, in which the nitrogen at position 17 comprises a secondary amine. It will be understood by one skilled in the art that the "nor" compound may be produced by methods known in the art or purchased as a starting material.
  • Non-limiting examples of normorphinans include norcodeine, normorphine, northebaine, nororipavine, noroxymorphone, nordihydromorphine, nordihydrocodeine, norhydrocodone, norhydromorphone, noroxycodone, nordextromethorphan, nordextrorphan, norlevomethorphan, norlevorphanol, norbuprenorphine, ⁇ oroxymomorphol, noroxycodol norsinomenine, nordihydrosinomenine, and combinations thereof.
  • the normorphinan comprises noroxymorphone.
  • the N-alkylated morphinan comprises any morphinan compound comprising a tertiary amine at position 17, wherein the amine at position 17 comprises a hydrocarbyl or substituted hydrocarbyl group.
  • Suitable examples of N-alkylated morphinans include, but are not limited to codeine, morphine, thebaine, oripavine, oxymorphone, dihydromorphone, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, oxycodeinone, naloxone, naltrexone, nalbuphine, naimefene, nalfurafine, morphinone, ethylmorphine, butorphanol, dextromethorphan, dextrorphan, levomethorphan, levorphanol, buprenorphine, sinomenine, dihydrosinomeni ⁇ e, and combinations thereof.
  • the N-alkylated morphinans
  • the R 10 group used to alkylate the nitrogen at position 17 is a hydrocarbyl or substituted hydrocarbyl group.
  • the R 10 group may be an alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, or aryl group.
  • the R 10 group may be methyl, cyciopropylmethyl, cyclobutylmethyl, or allyl.
  • the process comprises formation of an intermediate compound comprising an iminium salt of the normorphinan compound, prior to the formation of the N-alkylated morphinan.
  • the iminium salt serves as the substrate for reduction by formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, or combinations thereof, thereby forming the N-alkylated morphinan.
  • the R 10 group of iminium salt may be an alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, or aryl group.
  • the R 10 group may be methyl, cyclopropylmethyl, cyclobutylmethyl, or allyl.
  • an N-alkylated morphinan comprising Formula (Ilia) is synthesized from a normorphinan comprising Formula (Ia).
  • Reaction Scheme 1 depicts the production of the compound comprising Formula (Ilia) in accordance with one aspect of the present invention:
  • R 2 , R e , and R 7 are independently selected from the group consisting of hydrogen, hydrocarby!, substituted hydrocarbyl, and ⁇ - ⁇ 0R 11 ;
  • R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ 0R 11 ;
  • R 5 is selected from the group consisting of hydrogen, and hydroxyl
  • R 10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl
  • R 11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy! protecting group
  • X is selected from the group consisting of oxygen and sulfur.
  • R 3 , R 4 , R 6 , and R 7 are each hydrogen and X is oxygen.
  • R 2 is preferably ⁇ - ⁇ OR 11 , wherein R 11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group.
  • R 5 is preferably hydroxy!.
  • R 10 is preferably alky!, cycloalkyi, cycloalkylmethyl, ally!, or aryl; or more preferably methyl, ally!, cyclopropylmethyl, or cyclobutylmethyl.
  • Representative compounds comprising Formula (Ilia) include, but are not limited to oxymorphone, dihydromorphone, hydrocodone, hydromorphone, oxycodone, oxycodeinone, naloxone, naltrexone, nalbuphine, nalmefene.
  • an N-alkylated morphinan comprising Formula (HIb) is synthesized from a normorphinan comprising Formula (Ib).
  • Reaction Scheme 2 depicts the production of the compound comprising Formula (I lib) in accordance with one aspect of the present invention: wherein:
  • R 1 , R 2 , R 6 , R 7 , and R 9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and ⁇ - ⁇ 0R 11 ;
  • R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydrocarby!, substituted hydrocarbyl, halogen, and ⁇ - ⁇ 0R 11 ;
  • R 6 is selected from the group consisting of hydrogen, and hydroxyl
  • R 8 is selected from the group consisting of ⁇ 0, and hydroxyl
  • R 10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl
  • R 11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group.
  • Representative compounds comprising Formula (HIb) include, but are not limited to butorphanol, dextromethorphan, dextrorphan, levomethorphan, and levorphanol.
  • the process of the invention commences with formation of a reaction mixture by combining the compound comprising Formulas (Ia) or (Ib) with an alkylating agent in the presence of a proton acceptor.
  • alkylating agents are suitable for use in the process of the invention.
  • the alkylating agent transfers an alkyl group from the alkylating agent to the nitrogen at position 17 of the normorphinan, and can therefore be thought of as any compound capable of transferring an alkyl group.
  • the alkylating agent may be an aldehyde, having the general formula R 10 CHO, wherein R 10 may be hydrocarbyl or substituted hydrocarbyl.
  • R 10 may be alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, aryl, cyclopropylmethyl, cyclobutylmethyl, or allyl.
  • aldehydes examples include, but are not limited to alkyl-aldehydes such as methanal, ethanal, propanal, substituted propanal, butanal, substituted butanal, pentanal, substituted pentanal, hexanal, substituted hexanal, heptanal, substituted heptanal, octanal, substituted octanal, nonanal, substituted nonanal, decanal, substituted decanal, undecanal, substituted undecana!, dodecanal, substituted dodecanal, and substituted variations thereof; cycloalkyl- aldehydes such as cyclopropanecarboxaidehyde, cyclobutanecarboxaldehyde, cyclopentanecarboxaldehyde.
  • alkyl-aldehydes such as methanal, ethanal, propanal, substituted propanal, butanal, substituted butanal
  • the alkylating agent may be cyclopropanecarboxaidehyde or cyclobutanecarboxaldehyde.
  • the mole-to-mole ratio of the compound comprising Formulas (Ia) or (Ib) to the alkylating agent can and will vary.
  • the mole-to-mole ratio of the compound comprising Formulas (Ia) or (Ib) to the alkylating agent may range from about 1 :0.5 to about 1 :5.
  • the ratio of compound comprising Formulas (Ia) or (Ib) to the alkylating agent may range from about 1 :1 to about 1 :2,
  • the mole-to-mole ratio of the compound comprising Formulas (Ia) or (Ib) to the alkylating agent may be about 1 :1.4.
  • the process of this invention additionally requires an agent for reducing the intermediate compound comprising Formula (Ha) or (lib).
  • the reducing agent will be formic acid, an ester of formic acid, an alkali salt of formic acid, formamide, mixtures of formic acid and a salt of formic acid, or any combination thereof.
  • Suitable esters of formic acid include but are not limited to methyl formate, ethyl formate, trimethyl formate, triethyl formate, methyl chloroformate, and the like.
  • suitable alkali salts of formic acid include sodium formate, lithium formate, potassium formate, and cesium formate.
  • the reducing agent may be formic acid.
  • the mole-to-mole ratio of the compound comprising Formula (Ia) or (Ib) to the reducing agent will range from about 1 :1 to about 1 :20. In a preferred embodiment, the mole-to-mole ratio of the compound comprising Formula (Ia) or (Ib) to the reducing agent may range from about 1 : 10 to about 1 :15. In an exemplary embodiment, the mole-to-mole ratio of the compound comprising Formula (Ia) or (Ib) to the reducing agent may be about 1 :12.
  • the process of this invention is also conducted in the presence of a proton acceptor.
  • the proton acceptor has a pKa of between about 7 and about 13, preferably between about 8 and about 10.
  • Representative proton acceptors that may be employed include, but are not limited to, borate salts (such as, for example, NaaBCb), di- and tri-basic phosphate salts (such as, for example, Na2HPU4 and Na3PO4), bicarbonate salts (such as, for example, NaHCOa 1 KHCO3, mixtures thereof, and the like), hydroxide salts (such as, for example, NaOH, KOH, mixtures thereof, and the like), carbonate salts (such as, for example, Na2CO3, K2CO3, mixtures thereof, and the like), alkyl amine bases (such as, for example, triethylamine, trimethylamine, tributylamine, diethylamine, and diisopropytethylamine), organic bases (such as,
  • the proton acceptor may be triethylamine, trimethylamine, tributylamine, or pyridine, in an exemplary embodiment, the proton acceptor may be triethylamine.
  • the mole-to-moie ratio of the compound comprising Formula (Ia) or (Ib) to the proton acceptor may range from about 1:1 to about 1 :20. In a preferred embodiment, the mole-to-mole ratio of the compound comprising Formula (ia) or (Ib) to the proton acceptor may range from about 1 :5 to about 1:10. In an exemplary embodiment, the mole-to-mote ratio of the compound comprising Formula (Ia) or (Ib) to the proton acceptor may be about 1 :8.
  • the process of this invention is generally conducted in the presence of a solvent.
  • the solvent may be a protic solvent, an aprotic solvent, or an organic solvent.
  • Suitable examples of protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n- butanol, s-butanol, f-butanol, formic acid, acetic acid, water, and combinations thereof.
  • Non-limiting examples of suitable aprotic solvents include acetone, acetonitrile, diethoxymethane, N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylpropionamide, I.S-dimethyl-a ⁇ . ⁇ .e- tetrahydro-2 ⁇ 1H)-pyrimidinone (DMPU), 1 ,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME) 1 dimethoxymethane, bis(2-methoxyethyl)ether, N,N-dimethy!acetamide (DMAC), 1,4-dioxane, N-methyl-2- pyrrolidinone (NMP), ethyl acetate, ethyl formate, ethyl methyl ketone, formamide, hexachloroaceto ⁇ e, hexamethylphosphoramide, methyl acetate, N
  • organic solvents include, but are not limited to, alkane and substituted alkane solvents ⁇ including cycloalkanes), aromatic hydrocarbons, esters, ethers, ketones, combinations thereof, and the like.
  • Specific organic solvents that may be employed include, for example, acetonitrile, benzene, butyl acetate, f-butyl methylether, f-butyl methylketone, chlorobenzene, chloroform, chloromethane, cyclohexane, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, diethylene glycol, fluorobenzene, heptane, hexane, isobutylmethylketone, isopropyl acetate, methylethylketone, methyltetrahydrofuran, penty!
  • the solvent may be the protic solvent methanol.
  • the weight ratio of the solvent to the compound comprising Formula (Ia) or (Ib) will range from about 0.5:1 to about 100:1. In preferred embodiments, the weight ratio of the solvent to the compound comprising Formula (Ia) or (Ib) may range from about 2:1 to about 5:1.
  • reaction may be conducted at a temperature that ranges from about 20" C to about 120° C for a period of time that is sufficient to convert a substantial portion of the compound comprising Formula (!a) or (Ib) to the compound comprising Formula (Ilia) or (HIb).
  • the reaction may be conducted at a temperature that ranges from about 40 ° C to about 100 ° C.
  • the reaction may be conducted at a temperature that ranges from about 50 ° C to about 80 ° C.
  • the reaction is allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, such as chromatography (e.g., HPLC).
  • a "completed reaction” generally means that the reaction mixture contains a significantly diminished amount of the compound comprising Formula (Ia) or (Ib) and a significantly increased amount of the compound comprising Formula (Ilia) or (lllb) compared to the amounts of each present at the beginning of the reaction.
  • the amount of the compound comprising Formula (Ia) of (Ib) remaining in the reaction mixture may be less than about 3%, and preferably less than about 1%,
  • the yield of the compound comprising Formula (Ilia) or (IHb) can and will vary. Typically, the yield of the compound comprising Formula (Ilia) or (lllb) may be at least about 50%, In preferred embodiments of the invention, the yield of the compound comprising Formula (Ilia) or (lllb) may be at least about 65%,
  • the reaction may also be performed in a one-pot process, whereby all reagents are added in one step to form the reaction mixture.
  • the reaction mixture comprises the compound comprising Formula (Ia) or (Ib), the alkylating agent, the proton acceptor, and the reducing agent, as defined above.
  • the one-pot process of the invention substantially eliminates the need to isolate or purify the intermediate compound comprising Formula (Ha) or (lib) and/or to manually add the reducing agent to the reaction mixture upon completion of the reaction with the alkylating reagent.
  • any of the compounds comprising any of Formulas (I) or (II) may have a (-) or (+) orientation with respect to the rotation of polarized light, based on whether the starting material used is in the (-) or (+) opiate absolute form. More specifically, each chiral center may have an R or an S configuration.
  • the compounds formed by the processes of the invention comprise morphinans. For purposes of illustration, the carbon atoms of a morphinan compound are numbered as diagrammed below.
  • These morphinan compounds are recognized to have an alpha face and a beta face.
  • Some compounds described herein may have at least three chiral centers, namely carbons C13, C14, and C9, provided that the C15 and C16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule. Additionally, if the compound comprises a heterocyclic ring between carbons C4 and C5, C5 may also be a chiral center. At each chiral center, the stereochemistry at the carbon atom is independently R or S.
  • Some compounds described herein may have at least four chiral centers, namely carbons C5, C9, C13, and C14. At each chiral center, the stereochemistry at the carbon atom is independently R or S.
  • the configuration of carbons 5, 13, 14, and 9, respectively, may be RRRR, RRRS, RRSR 1 RSRR, SRRR 1 RRSS, RSSR, SSRR 1 SRRS, SRSR 1 RSRS, RSSS, SRSS, SSRS 1 SSSR, or SSSS, provided that the C15 and C16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule.
  • the nitrogen at position 17 may be either R or S, and depending on the R8 group chosen, C6 may also be a chiral center, with a stereochemistry of either R or S,
  • Additional compounds described herein may have at least three chiral centers, namely carbons C13, C14, and C9.
  • the stereochemistry at the carbon atom is independently R or S.
  • the configuration of carbons 13, 14, and 9, respectively, may be RRR, RRS 1 RSR, SRR, SRS, SSR 1 RSS, or SSS, provided that the C15 and C16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule.
  • the nitrogen at position 17 may be either R or S, and depending on the R8 group chosen, C6 may also be a chiral center, with a stereochemistry of either R or S.
  • the compounds described herein may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic form.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chirai, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
  • acyl denotes the moiety formed by removal of the hydroxy group from the group COOH of an organic carboxylic acid, e.g., RC(O) , wherein R is R 1 , R 1 O-, R 1 R 2 N-, or R 1 S-, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R 2 is hydrogen, hydrocarbyi or substituted hydrocarbyl,
  • acyioxy as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(O)O- wherein R is as defined in connection with the term "acyl.”
  • O oxygen linkage
  • alkyl as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
  • alkenyl as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyi, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • alkynyl as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
  • aromatic as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic aromatic groups. These aromatic groups are preferably monocyclic, bicyclic, or tricyclic groups containing from 6 to 14 atoms in the ring portion.
  • aromatic encompasses the "aryi” and “heteroaryl” groups defined below.
  • aryl or “Ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl, Phenyi and substituted phenyl are the more preferred aryl.
  • halogen or halo as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
  • heteroatom shall mean atoms other than carbon and hydrogen.
  • heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non- aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom.
  • Exemplary heterocyclo groups include heteroaromatics as described below.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano, ketals, acetals, esters and ethers.
  • heteroaryl as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heteroaryl group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon.
  • hydrocarbon and “hydrocarbyi” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
  • protecting group denotes a group capable of protecting an oxygen atom, wherein the protecting group may be removed, subsequent to the reaction for which protection is employed, without disturbing the remainder of the molecule.
  • protecting groups include ethers ⁇ e.g., allyl, triphenylmethyl ⁇ trityl or Tr), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), ⁇ -methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-tri methy lsily Ieth oxym ethyl (SEM)), esters (e.g., benzoate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate
  • TMS trimethylsiiyl
  • TES triethylsilyl
  • TIPS triisopropylsilyl
  • TPS triphenylsilyl
  • TDMS t-buty Id imethy Is i Iy]
  • TDPS t-butyldiphenylsilyl
  • substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom.
  • substituents include halogen, heterocyclo, alkoxy, aikenoxy, aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, amido, nitro, cya ⁇ o, ketals, acetals, esters and ethers.
  • reaction mixture was removed from heating and a sample was taken. Approximateiy one drop of the reaction mixture was placed in 0.5 mL of 1% acetic acid, to prepare a sample for verification of reaction product. Upon sample analysis, it was shown to have a mass recovery of approximately 96%, Testing by high performance liquid chromatography (HPLC) revealed a naltrexone concentration of approximately 73% (w/w) of the sample, resulting in a yield of approximately 70%.
  • HPLC high performance liquid chromatography
  • the vial containing the reaction product was placed in a vacuum oven at ambient temperature under approximately 40 mm Hg vacuum pressure to further dry the sample. After approximateiy 19 hours in the vacuum oven, the sample was removed resulting in a tan solid weighing approximately 0.570 grams, which was subsequently verified to be naltrexone by HPLC assay.
  • the mixture was added to the test tube containing the noroxymorphone and methanol mixture at a temperature of approximately 8 ° C.
  • the combined reaction mixture was then heated by means of a J-Kem Personal Reaction Station (PRS) under an inert nitrogen environment.
  • the temperature of the heating block was 74 ° C, but the internal temperature of the reaction mixture was measured at 72 ° C. Additionally, the temperature of the upper block was chilled to 0 ° C, and the reaction mixture was allowed to react.
  • PRS J-Kem Personal Reaction Station
  • reaction mixture was removed from heating and a sample was taken. Approximately one drop of the reaction mixture was placed in 0.5 mL of 1% acetic acid, to prepare a sample for verification of reaction product. Upon analysis, the sample was shown to have a mass recovery of approximately 108%. Testing by high performance liquid chromatography (HPLC) revealed a 6- ketonalbuphine concentration of approximately 77% (w/w) of the sample, resulting in a yield of approximately 83%.
  • HPLC high performance liquid chromatography
  • the vial containing the reaction product was placed in a vacuum oven at ambient temperature under approximately 40 mm Hg vacuum pressure to further dry the sample. After approximately 19 hours in the vacuum oven, the sample was removed resulting in a tan solid weighing approximately 0.666 grams, which was subsequently verified to be 6-ketonalbu ⁇ hine by HPLC assay.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Addiction (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a process for the N-alkylation of normorphinan compounds to produce N-alkyiated morphinan compounds. In particular, the process relates to the alkylation of a normorphinan compound by a carboxaldehyde in the presence of a reducing agent to form an N-alkylated morphinan.

Description

PROCESS FOR THE REDUCTIVE ALKYLATION OF NORMORPHINANS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 61/153,021 filed
February 17, 2009, which is incorporated herein in its entirety.
FIELD OF INVENTION
[0002] The present invention generally relates to a method for the synthesis of N-alkylated morphinans. In particular, the process provides a method for reducing an iminium salt formed from the reaction of a normorphinan and a carboxaldehyde,
BACKGROUND OF THE INVENTION
[0003] N-aikylated morphinans are important pharmaceuticals, typically used as analgesics, opiate agonists, and opiate antagonists. With the increasing use of these agents, a practical and effective method of preparation of these compounds is vital to synthesizing diverse N-alkyl substituted morphinans.
[0004] Currently, the methods for synthesis of N-alkylated morphinans known in the art have at least one of two primary limitations: (a) their dependence on a transition metal catalyst, and (b) the use of hydrogen gas as a source of hydrogen for the alkylation. Transition metal catalysts are expensive and toxic, which requires testing of the finished product to ensure that the final product does not contain more than a specified parts per million of the transition metal, Additionally, hydrogen gas is hazardous, and methods of synthesis typically employ high pressures. Some prior art methods have incorporated a borohydride to catalyze the reaction. It was desired to avoid this method because the side products are difficult to separate from the desired product, and the reactions may require lower temperatures, -20° to - 30° C, when a keto group is present. In light of the current limitations, there is a need for an efficient, cost- effective method of the synthesis of N-alkylated normorphinans.
SUMMARY OF THE INVENTION
[0005] The present invention provides processes for the synthesis of N-alkylated morphinans from the corresponding normorphinan compounds. [0006] One aspect of the present invention encompasses a process for the preparation of an N- aikylated morphinan. The method comprises contacting a normorphinan comprising a secondary amine at position 17 with an alkylating agent comprising R10, wherein R10 is selected from the group consisting of hydrocarbyi and substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form the N-alkylated morphinan comprising NR10 at position 17.
[0007] In an additional aspect, the current invention encompasses a process for the preparation of a compound comprising Formula (IiIa). The process comprises: (a) contacting a compound comprising Formuia (Ia) with an alkylating agent comprising R10 in the presence of a proton acceptor to form a compound comprising Formula (Ha); and (b) contacting the compound comprising Formula (Ha) with a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form a compound comprising Formuia (Ilia) according to the following reaction scheme:
wherein: R2, R6, and R7 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {-}0R11;
R3, and R4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {-}0R11;
R5 is selected from the group consisting of hydrogen, and hydroxyl; R8 is selected from the group consisting of {=}0, and hydroxyl; Rio is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group; and
X is selected from the group consisting of oxygen and sulfur.
[0008] In another aspect the current invention encompasses a process for the preparation of a compound comprising Formula (lllb). The process comprises: (a) contacting a compound comprising Formula (Ib) with an alkylating agent comprising R10 in the presence of a proton acceptor to form a compound comprising Formula (lib); and (b) contacting the compound comprising Formula (lib) with a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form a compound comprising Formula (IHb) according to the following reaction scheme:
(INb) wherein:
R1, R2, R6, R7, and R9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {-}0R11;
R3, and R4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and HOR11;
R5 is selected from the group consisting of hydrogen, and hydroxyl;
R6 is selected from the group consisting of {=}0, and hydroxyl;
R10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and
R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy! protecting group.
DETAILED DESCRIPTION
[0009] The present invention provides an efficient process for the production of N-alkylated morphinans in high yield, In particular, the process of the present invention avoids the use of toxic metal catalysts and dangerous hydrogen gas. Moreover, the process of the invention may be conducted in a one-pot process, without isolation or purification of the intermediate products.
(a) Process for the synthesis of N-alkylated morphinans
[0010] One aspect of the present invention provides an efficient process for the production of N- alkylated morphinan compounds. The process comprises contacting a normorphinan comprising a secondary amine at position 17 with an alkylating agent comprising R10, wherein R10 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof to form the N-alkylated morphinan comprising NR10 at position 17.
[0011] Generally, the normorphinan comprises any compound having a morphinan structure, in which the nitrogen at position 17 comprises a secondary amine. It will be understood by one skilled in the art that the "nor" compound may be produced by methods known in the art or purchased as a starting material. Non-limiting examples of normorphinans include norcodeine, normorphine, northebaine, nororipavine, noroxymorphone, nordihydromorphine, nordihydrocodeine, norhydrocodone, norhydromorphone, noroxycodone, nordextromethorphan, nordextrorphan, norlevomethorphan, norlevorphanol, norbuprenorphine, πoroxymomorphol, noroxycodol norsinomenine, nordihydrosinomenine, and combinations thereof. In a preferred embodiment, the normorphinan comprises noroxymorphone.
[0012] The N-alkylated morphinan comprises any morphinan compound comprising a tertiary amine at position 17, wherein the amine at position 17 comprises a hydrocarbyl or substituted hydrocarbyl group. Suitable examples of N-alkylated morphinans include, but are not limited to codeine, morphine, thebaine, oripavine, oxymorphone, dihydromorphone, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, oxycodeinone, naloxone, naltrexone, nalbuphine, naimefene, nalfurafine, morphinone, ethylmorphine, butorphanol, dextromethorphan, dextrorphan, levomethorphan, levorphanol, buprenorphine, sinomenine, dihydrosinomeniπe, and combinations thereof. In a preferred embodiment, the N-alkylated morphinan comprises naltrexone, nalbuphine, or 6-ketonalbuphine.
[0013] In general, the R10 group used to alkylate the nitrogen at position 17 is a hydrocarbyl or substituted hydrocarbyl group. In a preferred embodiment, the R10 group may be an alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, or aryl group. In an exemplary embodiment, the R10 group may be methyl, cyciopropylmethyl, cyclobutylmethyl, or allyl. [0014] The process comprises formation of an intermediate compound comprising an iminium salt of the normorphinan compound, prior to the formation of the N-alkylated morphinan. The iminium salt serves as the substrate for reduction by formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, or combinations thereof, thereby forming the N-alkylated morphinan. The iminium salt is generally considered a protonated or substituted imine compound comprising the formula N+=CR10 at position 17, wherein R10 is a hydrocarbyl or substituted hydrocarbyl group as defined above. In a preferred embodiment, the R10 group of iminium salt may be an alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, or aryl group. In an exemplary embodiment, the R10 group may be methyl, cyclopropylmethyl, cyclobutylmethyl, or allyl.
(b) Synthesis of Compounds Comprising Formula (Ilia)
[0015] In one embodiment, an N-alkylated morphinan comprising Formula (Ilia) is synthesized from a normorphinan comprising Formula (Ia). For purposes of illustration, Reaction Scheme 1 depicts the production of the compound comprising Formula (Ilia) in accordance with one aspect of the present invention:
(Ilia) wherein:
R2, Re, and R7 are independently selected from the group consisting of hydrogen, hydrocarby!, substituted hydrocarbyl, and {-}0R11;
R3, and R4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {-}0R11;
R5 is selected from the group consisting of hydrogen, and hydroxyl; R8 is selected from the group consisting of {=}0, and hydroxy!; R10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy! protecting group; and
X is selected from the group consisting of oxygen and sulfur. [0016] In preferred iterations, R3, R4, R6, and R7 are each hydrogen and X is oxygen. R2 is preferably {-}OR11, wherein R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group. R5 is preferably hydroxy!. R8 is preferably {=}O. Furthermore, R10 is preferably alky!, cycloalkyi, cycloalkylmethyl, ally!, or aryl; or more preferably methyl, ally!, cyclopropylmethyl, or cyclobutylmethyl. In one exemplary embodiment, R3, R4, R6, and R7 are each hydrogen, X is oxygen, R2 is hydroxyl, R5 is {-OH}, R8 is {=}O, and R10 is cyclopropylmethyl. In another exemplary embodiment, R3, R4, R6, and R7 are each hydrogen, X is oxygen, R2 is {-}OH, R5 is {-}OH, R8 is {=}(_), and R10 is cyclobutylmethyl.
[0017] Representative compounds comprising Formula (Ilia) include, but are not limited to oxymorphone, dihydromorphone, hydrocodone, hydromorphone, oxycodone, oxycodeinone, naloxone, naltrexone, nalbuphine, nalmefene.
(c) Synthesis of Compound Comprising Formula (HIb)
[0018] In an additional embodiment, an N-alkylated morphinan comprising Formula (HIb) is synthesized from a normorphinan comprising Formula (Ib). For purposes of illustration, Reaction Scheme 2 depicts the production of the compound comprising Formula (I lib) in accordance with one aspect of the present invention: wherein:
R1, R2, R6, R7, and R9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {-}0R11;
R3, and R4 are independently selected from the group consisting of hydrogen, hydrocarby!, substituted hydrocarbyl, halogen, and {-}0R11;
R6 is selected from the group consisting of hydrogen, and hydroxyl; R8 is selected from the group consisting of {~}0, and hydroxyl; R10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and
R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group.
[0019] In preferred embodiments, R3, R4, and R6 are each hydrogen. Additionally, R1 is preferably hydrogen or hydroxyl. R2 is preferably {-}OR11, wherein R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy! protecting group. R7 is preferably hydrogen or f}OR11. R8 is preferably hydroxyl or (=}0. R10 is preferably alkyl, cycloalkyl, cycloalkylmethyl, ally!, or aryi; or more preferably methyl, allyl, cyclopropylmethyl, orcyclobutylmethyl.
[0020] Representative compounds comprising Formula (HIb) include, but are not limited to butorphanol, dextromethorphan, dextrorphan, levomethorphan, and levorphanol.
(d) Reaction Mixture
[0021] The process of the invention commences with formation of a reaction mixture by combining the compound comprising Formulas (Ia) or (Ib) with an alkylating agent in the presence of a proton acceptor. A variety of alkylating agents are suitable for use in the process of the invention. Generally, the alkylating agent transfers an alkyl group from the alkylating agent to the nitrogen at position 17 of the normorphinan, and can therefore be thought of as any compound capable of transferring an alkyl group. In a preferred embodiment, the alkylating agent may be an aldehyde, having the general formula R10CHO, wherein R10 may be hydrocarbyl or substituted hydrocarbyl. In preferred embodiments, R10 may be alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, aryl, cyclopropylmethyl, cyclobutylmethyl, or allyl. Examples of aldehydes that may be used include, but are not limited to alkyl-aldehydes such as methanal, ethanal, propanal, substituted propanal, butanal, substituted butanal, pentanal, substituted pentanal, hexanal, substituted hexanal, heptanal, substituted heptanal, octanal, substituted octanal, nonanal, substituted nonanal, decanal, substituted decanal, undecanal, substituted undecana!, dodecanal, substituted dodecanal, and substituted variations thereof; cycloalkyl- aldehydes such as cyclopropanecarboxaidehyde, cyclobutanecarboxaldehyde, cyclopentanecarboxaldehyde. cyclohexancarboxaldehyde, cycloheptanecarboxaldehyde, cyclooctanecarboxaldehyde, cyclononanecarboxaldehyde, cyclodecanecarboxaldehyde, benzalaldehyde, cinnamaldehyde, tolualdehyde (4-methylbenzaldehyde), and substituted variations thereof; and aldehydes having two terminal carbonyl groups such as ethanedial, propanedial, butanedial, pentanedial, hexanedial, heptanedial, octaπedial, nonanedial, decanedial, undecanedial, dodecanedial, and substituted variations thereof. In a preferred embodiment, the alkylating agent may be cyclopropanecarboxaidehyde or cyclobutanecarboxaldehyde.
[0022] The mole-to-mole ratio of the compound comprising Formulas (Ia) or (Ib) to the alkylating agent can and will vary. In general, the mole-to-mole ratio of the compound comprising Formulas (Ia) or (Ib) to the alkylating agent may range from about 1 :0.5 to about 1 :5. In a preferred embodiment, the ratio of compound comprising Formulas (Ia) or (Ib) to the alkylating agent may range from about 1 :1 to about 1 :2, In an exemplary embodiment, the mole-to-mole ratio of the compound comprising Formulas (Ia) or (Ib) to the alkylating agent may be about 1 :1.4.
[0023] The process of this invention additionally requires an agent for reducing the intermediate compound comprising Formula (Ha) or (lib). In general, the reducing agent will be formic acid, an ester of formic acid, an alkali salt of formic acid, formamide, mixtures of formic acid and a salt of formic acid, or any combination thereof. Suitable esters of formic acid include but are not limited to methyl formate, ethyl formate, trimethyl formate, triethyl formate, methyl chloroformate, and the like. Non-limiting examples of suitable alkali salts of formic acid include sodium formate, lithium formate, potassium formate, and cesium formate. In an exemplary embodiment, the reducing agent may be formic acid.
[0024] Generally, the mole-to-mole ratio of the compound comprising Formula (Ia) or (Ib) to the reducing agent will range from about 1 :1 to about 1 :20. In a preferred embodiment, the mole-to-mole ratio of the compound comprising Formula (Ia) or (Ib) to the reducing agent may range from about 1 : 10 to about 1 :15. In an exemplary embodiment, the mole-to-mole ratio of the compound comprising Formula (Ia) or (Ib) to the reducing agent may be about 1 :12.
[0025] The process of this invention is also conducted in the presence of a proton acceptor. In general, the proton acceptor has a pKa of between about 7 and about 13, preferably between about 8 and about 10. Representative proton acceptors that may be employed include, but are not limited to, borate salts (such as, for example, NaaBCb), di- and tri-basic phosphate salts (such as, for example, Na2HPU4 and Na3PO4), bicarbonate salts (such as, for example, NaHCOa1 KHCO3, mixtures thereof, and the like), hydroxide salts (such as, for example, NaOH, KOH, mixtures thereof, and the like), carbonate salts (such as, for example, Na2CO3, K2CO3, mixtures thereof, and the like), alkyl amine bases (such as, for example, triethylamine, trimethylamine, tributylamine, diethylamine, and diisopropytethylamine), organic bases (such as, for example, pyridine, N-methylmorpholine, N,N-dimethylaminopyridine, and mixtures thereof), organic buffers (such as, for example, N-(2-acetamido)-2-aminoethane sulfonic acid (ACES), N-(2-acetamido)- iminodiacetic acid (ADA), N,N-bis(2-hydroxyethyi)glycine (BIClNE), 3-(cycIohexylamino)-1-propanesulfonic acid (CAPS), 2-(cyclohexylamino) ethanesulfonic acid (CHES), 4-(2-hydroxyethyl)-1- piperazinepropanesulfonic acid (EPPS), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), 2-(4-morρholinyl) ethanesulfonic acid (MES)14-morpholinepropanesulfonic acid (MOPS), 1,4- piperazinediethanesulfonic acid (PIPES), [(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1- propanesulfonic acid (TAPS), 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), salts and/or mixtures thereof, and the like), and combinations thereof. In a preferred embodiment, the proton acceptor may be triethylamine, trimethylamine, tributylamine, or pyridine, in an exemplary embodiment, the proton acceptor may be triethylamine. The mole-to-moie ratio of the compound comprising Formula (Ia) or (Ib) to the proton acceptor may range from about 1:1 to about 1 :20. In a preferred embodiment, the mole-to-mole ratio of the compound comprising Formula (ia) or (Ib) to the proton acceptor may range from about 1 :5 to about 1:10. In an exemplary embodiment, the mole-to-mote ratio of the compound comprising Formula (Ia) or (Ib) to the proton acceptor may be about 1 :8.
[0026] In addition, the process of this invention is generally conducted in the presence of a solvent. The solvent may be a protic solvent, an aprotic solvent, or an organic solvent. Suitable examples of protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n- butanol, s-butanol, f-butanol, formic acid, acetic acid, water, and combinations thereof. Non-limiting examples of suitable aprotic solvents include acetone, acetonitrile, diethoxymethane, N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylpropionamide, I.S-dimethyl-a^.δ.e- tetrahydro-2{1H)-pyrimidinone (DMPU), 1 ,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME)1 dimethoxymethane, bis(2-methoxyethyl)ether, N,N-dimethy!acetamide (DMAC), 1,4-dioxane, N-methyl-2- pyrrolidinone (NMP), ethyl acetate, ethyl formate, ethyl methyl ketone, formamide, hexachloroacetoπe, hexamethylphosphoramide, methyl acetate, N-methylacetamide, N-methylformamide, methylene chloride, nitrobenzene, nitromethane, propionitrile, sulfolane, tetramethylurea, tetrahydrofuran (THF)1 2-methyl tetrahydrofuran, toluene, trichloromethane, and combinations thereof. Suitable examples of organic solvents include, but are not limited to, alkane and substituted alkane solvents {including cycloalkanes), aromatic hydrocarbons, esters, ethers, ketones, combinations thereof, and the like. Specific organic solvents that may be employed, include, for example, acetonitrile, benzene, butyl acetate, f-butyl methylether, f-butyl methylketone, chlorobenzene, chloroform, chloromethane, cyclohexane, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, diethylene glycol, fluorobenzene, heptane, hexane, isobutylmethylketone, isopropyl acetate, methylethylketone, methyltetrahydrofuran, penty! acetate, n-propyl acetate, tetrahydrofuran, toluene, and combinations thereof. In a preferred embodiment, the solvent may be the protic solvent methanol. In general, the weight ratio of the solvent to the compound comprising Formula (Ia) or (Ib) will range from about 0.5:1 to about 100:1. In preferred embodiments, the weight ratio of the solvent to the compound comprising Formula (Ia) or (Ib) may range from about 2:1 to about 5:1.
(e) Reaction Conditions [0027] In general, the reaction may be conducted at a temperature that ranges from about 20" C to about 120° C for a period of time that is sufficient to convert a substantial portion of the compound comprising Formula (!a) or (Ib) to the compound comprising Formula (Ilia) or (HIb). In a preferred embodiment, the reaction may be conducted at a temperature that ranges from about 40° C to about 100° C. !n an exemplary embodiment, the reaction may be conducted at a temperature that ranges from about 50° C to about 80° C.
[0028] Typically, the reaction is allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, such as chromatography (e.g., HPLC). In this context, a "completed reaction" generally means that the reaction mixture contains a significantly diminished amount of the compound comprising Formula (Ia) or (Ib) and a significantly increased amount of the compound comprising Formula (Ilia) or (lllb) compared to the amounts of each present at the beginning of the reaction. Typically, the amount of the compound comprising Formula (Ia) of (Ib) remaining in the reaction mixture may be less than about 3%, and preferably less than about 1%,
[0029] The yield of the compound comprising Formula (Ilia) or (IHb) can and will vary. Typically, the yield of the compound comprising Formula (Ilia) or (lllb) may be at least about 50%, In preferred embodiments of the invention, the yield of the compound comprising Formula (Ilia) or (lllb) may be at least about 65%,
[0030] The reaction may also be performed in a one-pot process, whereby all reagents are added in one step to form the reaction mixture. Accordingly, the reaction mixture comprises the compound comprising Formula (Ia) or (Ib), the alkylating agent, the proton acceptor, and the reducing agent, as defined above. The one-pot process of the invention substantially eliminates the need to isolate or purify the intermediate compound comprising Formula (Ha) or (lib) and/or to manually add the reducing agent to the reaction mixture upon completion of the reaction with the alkylating reagent.
(f) Stereochemistry and Eπantiomers
[0031] Any of the compounds comprising any of Formulas (I) or (II) may have a (-) or (+) orientation with respect to the rotation of polarized light, based on whether the starting material used is in the (-) or (+) opiate absolute form. More specifically, each chiral center may have an R or an S configuration. The compounds formed by the processes of the invention comprise morphinans. For purposes of illustration, the carbon atoms of a morphinan compound are numbered as diagrammed below.
[0032] These morphinan compounds are recognized to have an alpha face and a beta face. Some compounds described herein, may have at least three chiral centers, namely carbons C13, C14, and C9, provided that the C15 and C16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule. Additionally, if the compound comprises a heterocyclic ring between carbons C4 and C5, C5 may also be a chiral center. At each chiral center, the stereochemistry at the carbon atom is independently R or S.
[0033] Some compounds described herein, such as compounds comprising Formula (Ia), (lia) and (Ilia), may have at least four chiral centers, namely carbons C5, C9, C13, and C14. At each chiral center, the stereochemistry at the carbon atom is independently R or S. The configuration of carbons 5, 13, 14, and 9, respectively, may be RRRR, RRRS, RRSR1 RSRR, SRRR1 RRSS, RSSR, SSRR1 SRRS, SRSR1 RSRS, RSSS, SRSS, SSRS1 SSSR, or SSSS, provided that the C15 and C16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule. Additionally, the nitrogen at position 17 may be either R or S, and depending on the R8 group chosen, C6 may also be a chiral center, with a stereochemistry of either R or S,
[0034] Additional compounds described herein, such as compounds comprising Formula (Ib)1 (lib), and (HIb), may have at least three chiral centers, namely carbons C13, C14, and C9. At each chiral center, the stereochemistry at the carbon atom is independently R or S. The configuration of carbons 13, 14, and 9, respectively, may be RRR, RRS1 RSR, SRR, SRS, SSR1 RSS, or SSS, provided that the C15 and C16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule. Additionally, the nitrogen at position 17 may be either R or S, and depending on the R8 group chosen, C6 may also be a chiral center, with a stereochemistry of either R or S. DEFINITIONS
[0035] To facilitate understanding of the invention, several terms are defined below:
[0036] The compounds described herein may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic form. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chirai, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
[0037] The term "acyl," as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxy group from the group COOH of an organic carboxylic acid, e.g., RC(O) , wherein R is R1, R1O-, R1R2N-, or R1S-, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R2 is hydrogen, hydrocarbyi or substituted hydrocarbyl,
[0038] The term "acyioxy," as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(O)O- wherein R is as defined in connection with the term "acyl."
[0039] The term "alkyl" as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
[0040] The term "alkenyl" as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyi, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
[0041] The term "alkynyl" as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
[0042] The term "aromatic" as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic aromatic groups. These aromatic groups are preferably monocyclic, bicyclic, or tricyclic groups containing from 6 to 14 atoms in the ring portion. The term "aromatic" encompasses the "aryi" and "heteroaryl" groups defined below. [0043] The term "aryl" or "Ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl, Phenyi and substituted phenyl are the more preferred aryl.
[0044] The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
[0045] The term "heteroatom" shall mean atoms other than carbon and hydrogen.
[0046] The terms "heterocyclo" or "heterocyclic" as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non- aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo groups include heteroaromatics as described below. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano, ketals, acetals, esters and ethers.
[0047] The term "heteroaryl" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaryl group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon.
[0048] The terms "hydrocarbon" and "hydrocarbyi" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
[0049] The term "protecting group" as used herein denotes a group capable of protecting an oxygen atom, wherein the protecting group may be removed, subsequent to the reaction for which protection is employed, without disturbing the remainder of the molecule. Exemplary protecting groups include ethers {e.g., allyl, triphenylmethyl {trityl or Tr), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-tri methy lsily Ieth oxym ethyl (SEM)), esters (e.g., benzoate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsiiylethyl carbonate), sily! ethers (e.g., trimethylsiiyl (TMS)1 triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), t-buty Id imethy Is i Iy] (TBDMS)1 t-butyldiphenylsilyl (TBDPS) and the like. A variety of protecting groups and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wilts, John Wiley & Sons, 1999.
[0050] The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, aikenoxy, aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, amido, nitro, cyaπo, ketals, acetals, esters and ethers.
[0051] When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.
[0052] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.
EXAMPLES
[0053] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Example 1: Production of naltrexone
[0054] A quantity of 0.50 grams noroxymorphone was placed within a test tube. A stir bar was added to the test tube, which was subsequently sealed with a rubber septum. Subsequently, 1.0 mL methanol was added to the test tube to create a reaction mixture. Next, 1.0 mL of methanol was mixed with 2.0 mL of triethylamine in a separate test tube, and the mixture was chilled in an ice bath. After the mixture was allowed to chill, 0.83 mL formic acid was added to the methanol and triethylamine mixture. During addition of formic acid, care was taken to ensure that the temperature of the mixture was less than 30° C. After addition of formic acid, 0.19 mL cyclopropanecarboxaldehyde (CPCA) was added to the mixture, with care to ensure that the temperature was maintained below 25° C.
[0055] Once the separate reaction mixture comprising methanol, triethylamine, formic acid, and CPCA mixture was formed, the mixture was added to the test tube containing the noroxymorphone and methanol mixture at a temperature of approximately 8° C. The combined reaction mixture was then heated by means of a J-Kem Personal Reaction Station (PRS) under an inert nitrogen environment. The temperature of the heating block was 74° C, but the internal temperature of the reaction mixture was measured at 72° C. Additionally, the temperature of the upper block was chilled to 0° C, and the reaction mixture was allowed to react,
[0056] After three hours, the reaction mixture was removed from heating and a sample was taken. Approximateiy one drop of the reaction mixture was placed in 0.5 mL of 1% acetic acid, to prepare a sample for verification of reaction product. Upon sample analysis, it was shown to have a mass recovery of approximately 96%, Testing by high performance liquid chromatography (HPLC) revealed a naltrexone concentration of approximately 73% (w/w) of the sample, resulting in a yield of approximately 70%.
[0057] Once the production of naltrexone was verified by the sample, 4.0 mL of water was added to the remaining reaction mixture. The reaction mixture was cooled to approximately 10° C in an ice bath and the pH was adjusted to approximately 9, using concentrated ammonium hydroxide. The product was then extracted using 8 mL of dichloromethane. The product-containing layer was then separated and the product was further extracted with 3 mL dichloromethane, Subsequently, the product plus additional organic extracts were gathered and washed with 2 mL water. The organic extracts were filtered through cotton and concentrated on a rotary evaporator (rotovap) to create a foamy yellow solid, weighing approximately 0.592 grams. Next, the vial containing the reaction product was placed in a vacuum oven at ambient temperature under approximately 40 mm Hg vacuum pressure to further dry the sample. After approximateiy 19 hours in the vacuum oven, the sample was removed resulting in a tan solid weighing approximately 0.570 grams, which was subsequently verified to be naltrexone by HPLC assay.
[0058] Thus, 0.50 grams of noroxymorphone was reacted according to the process described above to produce 0.570 grams naltrexone. Example 2; Production of 6-ketonalbuphine
[0059] A quantity of 0.50 grams noroxymorphone was placed within a test tube. A stir bar was added to the test tube, which was subsequently sealed with a rubber septum. Subsequently, 1.0 mL methanol was added to the test tube to create a reaction mixture. Next, 1.0 mL of methanol was mixed with 2.0 mL of triethylamine in a separate test tube, and the mixture was chilled in an ice bath. After the mixture was allowed to chill, 0.83 mL formic acid was added to the methanol and triethylamine mixture. During addition of formic acid, care was taken to ensure that the temperature of the mixture was less than 30° C. After addition of formic acid, 0.19 mL cyclobutanecarboxaldehyde (CBCA) was added to the mixture, with care to ensure that the temperature was maintained below 25° C.
[0060] Once the separate reaction mixture comprising methanol, triethylamine, formic acid, and CBCA mixture was formed, the mixture was added to the test tube containing the noroxymorphone and methanol mixture at a temperature of approximately 8° C. The combined reaction mixture was then heated by means of a J-Kem Personal Reaction Station (PRS) under an inert nitrogen environment. The temperature of the heating block was 74° C, but the internal temperature of the reaction mixture was measured at 72° C. Additionally, the temperature of the upper block was chilled to 0° C, and the reaction mixture was allowed to react.
[0061] After three hours, the reaction mixture was removed from heating and a sample was taken. Approximately one drop of the reaction mixture was placed in 0.5 mL of 1% acetic acid, to prepare a sample for verification of reaction product. Upon analysis, the sample was shown to have a mass recovery of approximately 108%. Testing by high performance liquid chromatography (HPLC) revealed a 6- ketonalbuphine concentration of approximately 77% (w/w) of the sample, resulting in a yield of approximately 83%.
[0062] Once the production of 6-ketonalbuphine was verified, 4.0 mL of water was added to the remaining reaction mixture, The reaction mixture was cooled to approximately 10° C in an ice bath and the pH was adjusted to approximately 9, using concentrated ammonium hydroxide. The product was then extracted using 8 mL of dichloromethane. The product-containing layer was then separated and the product was further extracted with 3 mL dichloromethane. Subsequently, the product plus additional organic extracts were gathered and washed with 2 mL water. The organic extracts were filtered through cotton and concentrated on a rotary evaporator (rotovap) to create a foamy tan solid, weighing approximately 0.685 grams. Next, the vial containing the reaction product was placed in a vacuum oven at ambient temperature under approximately 40 mm Hg vacuum pressure to further dry the sample. After approximately 19 hours in the vacuum oven, the sample was removed resulting in a tan solid weighing approximately 0.666 grams, which was subsequently verified to be 6-ketonalbuρhine by HPLC assay.
[0063] Thus, 0.50 grams of noroxymorphone was reacted according to the process described above to produce 0.666 grams 6-ketonalbuphine.

Claims

CLAIMS:What Is Claimed Is:
1. A process for the preparation of an N-alkylated morphinan comprising NR10 at position 17, the process comprising contacting a normorphinan comprising a secondary amine at position 17 with an alkylating agent comprising R10, wherein R10 is chosen from hydracarbyl and substituted hydrocarbyl, a proton acceptor, and a reducing agent chosen from formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof to form the N-alkylated morphinan comprising NR10 at position 17.
2. The process of claim 1 , wherein the normorphinan is chosen from norcodeine, πormorphine, northebaine, noraripavine, noroxymorphone, nordihydromorphine, nordihydrocodeine, norhydrocodone, norhydromorphone, noroxycodone, nordextromethorphan, nordextrorphan, norlevomethorphan, norlevorphanol, norbuprenorphine, noroxymomorphol, noroxycodol, norsinomenine, and nordihydrosinomenine; the N-alkylated morphinan is chosen from codeine, morphine, thebaine, oripavine, oxymorphone, dihydromorphone, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, oxycodeinone, naloxone, naltrexone, nalbuphine, nalmefene, nalfurafine, morphinone, ethylmorphine, butorphanot, dextromethorphan, dextrorphan, levomethorphan, levorphanol, buprenorphine, sinomenine, and dihydrosinomenine; the alkylating agent comprises an aldehyde; and R10 is chosen from alkyl, cycloalkyl, cycioalkylmethyl, alkenyl, alkynyl, and aryl.
3. The process of claim 1 or 2, wherein the normorphinan is chosen from norcodeine, normorphine, northebaine, noroxymorphone, nordihydromorphine, nordihydrocodeine, norhydrocodone, norhydromorphone, noroxycodone, nordextromethorphan, nordextrorphan, norlevomethorphan, norlevorphanol, norsinomenine, and nordihydrosinomenine; the proton acceptor is triethylamiπe; the alkylating agent comprises an aldehyde, and R10 is chosen from atkyl, cycloalkyl, cycioalkylmethyl, alkenyl, alkynyl, and aryl.
4. The process of any of claims 1 to 3, wherein an intermediate compound comprising an iminium salt of the normorphinan is formed in the reaction prior to the formation of the N-alkylated morphinan.
5. The process of claim 4, wherein the N-alkylated morphinan comprises Formula (ilia), the process comprising:
(a) contacting the normorphinan comprising Formula (Ia) with the alkylating agent comprising R10 in the presence of the proton acceptor to form the intermediate compound comprising Formula (Ha); and
(b) contacting the compound comprising Formula (Ha) with the reducing agent chosen from formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form the compound comprising Formula (Ilia) according to the following reaction scheme:
(Ilia) wherein:
R2, R6, and Rr are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and {-}0R11;
R3, and R4 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {-}0R11;
R5 is chosen from hydrogen, and hydroxyl;
R8 is chosen from {=}0, and hydroxyl;
R11 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group; and
X is chosen from oxygen and sulfur.
6. The process of claim 5, wherein R3, R4, R6, and R7 are hydrogen, R8 is {=}0, R10 is a cycloatky! group, and X is oxygen.
7. The process of claim 5, wherein R3, R4, R6, and R7 are hydrogen, R8 is a hydroxyl group, R10 is a cycloalkylmethyl group, and X is oxygen.
8. The process of any of claims 5 to 7, wherein the optical activity of compounds comprising Formulas (Ia), (Ha), and (Ilia) is (-} or (+), and the configuration of carbons 5, 13, 14, and 9, respectively, is chosen from RRRR, RRRS1 RRSR1 RSRR, SRRR, RRSS1 RSSR1 SSRR1 SRRS, SRSR, RSRS1 RSSS, SRSS1 SSRS, SSSR1 and SSSS, provided that the carbons at positions 15 and 16 are both either on the alpha face of the molecule or the beta face of the molecule.
9. The process of claim 4, wherein the N-alkylated morphinan comprises Formula (HIb), the process comprising:
(a) contacting the normorphinan comprising Formula (Ib) with the alkylating agent comprising R10 in the presence of the proton acceptor to form the intermediate compound comprising Formula (lib); and
(b) contacting the compound comprising Formula (lib) with the reducing agent chosen from formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof to form the compound comprising Formula (lllb) according to the following reaction scheme:
Alkylating Agent
Proton Acceptor
wherein:
R1, R2, R6, R7, and Ra are independently chosen from hydrogen, hydracarbyl, substituted hydrocarbyl, and {-}0R11; R3, and R4 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {-}0R11;
R5 is chosen from hydrogen, and hydroxy!;
R8 is chosen from {=}0, and hydroxyl; and
R11 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting group.
10. The process of claim 9, wherein R1, R3, R4, R6, R7, and R9 are hydrogen, R8 is {=}O, and R10is a cycloalkyl group.
11. The process of claim 9, wherein R1, R3, R4, R6, R7, and R9 are hydrogen, R8 is a hydroxyl group, and R10 is a cycloalkylmethyl group.
12. The process of any of claims 9 to 11, wherein the optical activity of compounds comprising Formulas (Ib), (lib), and (HIb) is (-) or (+) and the configuration of C13, CH, and C9, respectively, is chosen from RRR, RRS. RSR, SRR, SRS, SSR, RSS, and SSS, provided that the carbons at positions 15 and 16 are both either on the alpha face of the molecule or the beta face of the molecule.
13. The process of any of claims 1 to 12, wherein the alkylating agent comprises an aldehyde comprising the formula R10CHO, the reducing agent is formic acid, and the reaction is performed in the presence of a protic solvent.
14. The process of any of claims 1 to 13, wherein the proton acceptor is triethylamine; the alkylating agent comprises a carboxaldehyde, R10 is chosen from cyclopropylmethyl and cyclobutylmethyl; and the reaction is conducted in the presence of a protic solvent comprising an alcohol group.
15. The process of any of claims 1 to 14, wherein the reaction is conducted in a one-pot process.
EP10704301.0A 2009-02-17 2010-02-17 Process for the reductive alkylation of normorphinans Not-in-force EP2398808B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL10704301T PL2398808T3 (en) 2009-02-17 2010-02-17 Process for the reductive alkylation of normorphinans

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15302109P 2009-02-17 2009-02-17
PCT/US2010/024372 WO2010096416A1 (en) 2009-02-17 2010-02-17 Process for the reductive alkylation of normorphinans

Publications (2)

Publication Number Publication Date
EP2398808A1 true EP2398808A1 (en) 2011-12-28
EP2398808B1 EP2398808B1 (en) 2013-11-20

Family

ID=42115354

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10704301.0A Not-in-force EP2398808B1 (en) 2009-02-17 2010-02-17 Process for the reductive alkylation of normorphinans

Country Status (8)

Country Link
US (1) US8431701B2 (en)
EP (1) EP2398808B1 (en)
JP (2) JP5778042B2 (en)
AU (1) AU2010216150B2 (en)
CA (1) CA2752744A1 (en)
ES (1) ES2440595T3 (en)
PL (1) PL2398808T3 (en)
WO (1) WO2010096416A1 (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8962841B2 (en) * 2007-06-29 2015-02-24 Brock University Methods for one-pot N-demethylation/N-functionalization of morphine and tropane alkaloids
PH12012502083A1 (en) 2010-05-10 2017-07-26 Euro Celtique Sa Manufacturing of active-free granules and tablets comprising the same
EP2568965A1 (en) 2010-05-10 2013-03-20 Euro-Celtique S.A. Combination of active loaded granules with additional actives
US9700508B2 (en) 2010-05-10 2017-07-11 Euro-Celtique S.A. Pharmaceutical compositions comprising hydromorphone and naloxone
FR2984320B1 (en) * 2011-12-20 2013-11-29 Servier Lab NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID
CN103387579A (en) * 2012-05-08 2013-11-13 长沙理工大学 Synthesis of 4-benzyloxy-17-benzenesulfonylmorphinan-6-one
CN103387539A (en) * 2012-05-08 2013-11-13 长沙理工大学 Synthesis of 4-benzyloxy-17-acetyl morphinan-6-one
CA2922723C (en) * 2013-09-25 2022-04-19 Mallinckrodt Llc Improved process for the preparation of radioiodinated 3-fluoropropyl-nor-b-cit
WO2015071380A1 (en) 2013-11-13 2015-05-21 Euro-Celtique S.A. Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome
US9701688B2 (en) 2014-05-05 2017-07-11 Noramco, Inc. Process for the preparation of opioid compounds
US9701687B2 (en) 2014-05-05 2017-07-11 Noramco, Inc. Process for the preparation of opioid compounds
CN109096190B (en) * 2017-06-21 2021-07-02 中国医学科学院药物研究所 A kind of sinomenine derivative and its preparation method, use and pharmaceutical composition

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2578787A (en) 1949-04-09 1951-12-18 Rohm & Haas Reduction of enamines
GB0421687D0 (en) 2004-09-30 2004-11-03 Johnson Matthey Plc Preparation of opiate analgesics
JP4994246B2 (en) 2006-01-18 2012-08-08 大塚化学株式会社 Method for producing tertiary amine
CA2652849A1 (en) * 2006-05-25 2007-12-06 Alpharma (Bermuda) Investments Ltd. Process useful in the preparation of morphinan antagonists
JP2010533719A (en) 2007-07-17 2010-10-28 マリンクロッド・インコーポレイテッド Preparation of N-alkylated opiates by reductive amination
NZ607842A (en) * 2008-09-30 2013-12-20 Mallinckrodt Llc Processes for the selective amination of ketomorphinans

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010096416A1 *

Also Published As

Publication number Publication date
WO2010096416A1 (en) 2010-08-26
ES2440595T3 (en) 2014-01-29
JP2012518013A (en) 2012-08-09
US8431701B2 (en) 2013-04-30
AU2010216150B2 (en) 2015-05-14
JP2015180661A (en) 2015-10-15
EP2398808B1 (en) 2013-11-20
PL2398808T3 (en) 2014-04-30
JP5778042B2 (en) 2015-09-16
AU2010216150A1 (en) 2011-09-08
CA2752744A1 (en) 2010-08-26
US20100210843A1 (en) 2010-08-19

Similar Documents

Publication Publication Date Title
US8431701B2 (en) Process for the reductive alkylation of normorphinans
JP5688974B2 (en) Processes and compounds for the production of (+)-opiates
US8080661B2 (en) Processes for the synthesis of tertiary amines
US8017777B2 (en) Process for the preparation of buprenorphine and derivatives for buprenorphine
CA2806596A1 (en) N-demethylation of 6-keto morphinans
EP2601195B1 (en) Tandem process for preparing n-alkyl morphinans
US9012468B2 (en) One pot process for producing 6-hydroxyl nal-opiate
AU2014348256B2 (en) Preparation of normorphinans

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110817

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20121221

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20130604

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: CH

Ref legal event code: NV

Representative=s name: RENTSCH PARTNER AG, CH

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 641576

Country of ref document: AT

Kind code of ref document: T

Effective date: 20131215

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602010011862

Country of ref document: DE

Effective date: 20140116

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2440595

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20140129

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20131120

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 641576

Country of ref document: AT

Kind code of ref document: T

Effective date: 20131120

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140320

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140220

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140320

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602010011862

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140217

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

26N No opposition filed

Effective date: 20140821

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602010011862

Country of ref document: DE

Effective date: 20140821

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140217

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20150220

Year of fee payment: 6

Ref country code: CH

Payment date: 20150226

Year of fee payment: 6

Ref country code: DE

Payment date: 20150226

Year of fee payment: 6

Ref country code: ES

Payment date: 20150226

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20150217

Year of fee payment: 6

Ref country code: PL

Payment date: 20150203

Year of fee payment: 6

Ref country code: TR

Payment date: 20150209

Year of fee payment: 6

Ref country code: GB

Payment date: 20150226

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20150226

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160229

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140221

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20100217

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602010011862

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20160217

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160229

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160229

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20161028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160217

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160217

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160229

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160901

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160217

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131120

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160217